Confirming a genetic diagnosis of cystic fibrosis (CF) for clinically affected individuals should be more accessible today, with more laboratories offering testing and improved technologies at lower costs. Instead, diagnostic testing for CF has become more complex due to the variety of genetic testing options available for the one known causative gene ( CFTR). This article provides an overview of genetic tests currently available for CF in six laboratories in South Africa (SA). Also, it demonstrates the evolution of CF tests used at one private laboratory in the country via a ten-year retrospective audit. The findings of this study may serve as a guide for healthcare providers (HCPs) in selecting appropriate testing for CF diagnostic genetic confirmation. The choice of genetic test and methodology depends on individualised factors such as the ethnic origin of the patient, test availability, advantages and limitations, and cost. The ethnic diversity of SA’s populations and probable under-reporting of CF in the country makes the diagnosis of this relatively common genetic condition complex. The actual burden of CF in SA is unknown, and comprehensive genetic testing, with an ongoing compilation of patient data in the SA CF registry, should assist in addressing the genetic diversity of CF-causing variants.